Update: Aktuelle klinische Entwicklungen bei pulmonaler Hypertonie

Zusammenfassung

Die therapeutischen Möglichkeiten bei Patienten mit Lungenhochdruck haben sich in den letzten Jahren deutlich verbessert. Jedoch muss bei jedem Patienten vor Einleitung einer Therapie eine ätiologische Zuordnung erfolgen. Die pulmonale arterielle Hypertonie (PAH; Gruppe 1 der Venedig-Klassifikation) ist von anderen Formen der pulmonalen Hypertonie (PH; Gruppen 2 – 5 der Venedig-Klassifikation) klar abzugrenzen. Zur Behandlung der PAH stehen mit Prostazyklin-Analoga (Prostanoide), Endothelin-Rezeptor-Antagonisten (ERA) und Phosphodiesterase-5-Inhibitoren mittlerweile Pharmaka aus drei verschiedenen Substanzklassen zur Verfügung, für die jeweils ein Wirksamkeitsnachweis erbracht wurde. Eine aktuelle Metaanalyse zeigt, dass durch diese Therapien erstaunlicherweise bereits innerhalb kurzer Beobachtungszeiträume eine Verbesserung der Überlebensrate erzielt werden kann. Dennoch weisen viele Patienten weiterhin eine erhebliche klinische Symptomatik und eine deutlich eingeschränkte Lebenserwartung auf. Im Folgenden soll ein Überblick über die aktuellen Entwicklungen bei zugelassenen Therapien der PAH, bei der Etablierung neuer Therapiekonzepte zur Behandlung der PAH, sowie zu den Therapiemöglichkeiten bei anderen Formen der PH gegeben werden.

Summary

During the last years, therapeutic options for the treatment of pulmonary arterial hypertension (PAH) have significantly improved. However, the therapeutic concept depends on the etiology of the disease, so that an exact classification is mandatory. Currently, three substance classes are approved for the treatment of PAH (Group I of the Venice Classification): Endothelin receptor antagonists, phosphodiesterase type-5 inhibitors, and prostanoids. After the World Conference in Dana Point (2008), recent changes in therapeutic strategies comprise the early treatment of the disease, as well as the increased importance of an early use of combination therapy if treatment goals are not met. Several new substances are currently evaluated in clinical trials. The soluble guanylate cyclase (sGC) stimulators achieve potent, NO-independent vasodilation. Another promising pathophysiological approach is currently evaluated by the use of tyrosine kinase inhibitors – anti-proliferative drugs which inhibit or even may reverse the pulmonary vascular remodeling process. Serotonin receptor antagonists are also reported to have anti-proliferative, anti-thrombotic and anti-fibrotic effects. Other forms of pulmonary hypertension (Groups II-V) are strictly separated from PAH. Evidence on treatment with PAH specific agents is strongly needed for these groups. Patients with non-PAH pulmonary hypertension should be referred to PAH expert centers, and preferably treated in controlled studies.

pulmonale arterielle Hypertonie - Tyrosinkinasen - Platelet-derived Growth Factor (PDGF) - sGC-Stimulator - Serotonin

pulmonary arterial hypertension - tyrosine kinase - platelet-derived growthfactor (PDGF) - sGC stimulator - serotonin

Literatur

• 1 Barst R J, Gibbs S R, Ghofrani H A. et al . Updated evidence-based treatment algorithm in pulmonary arterial hypertension.  J Am Coll Cardiol. 2009;  54 (Suppl S) S78-S84
• 2 Evgenov O V, Pacher P, Schmidt P M, Hasko G, Schmidt H H, Stasch J P. NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential.  Nat Rev Drug Discov. 2006;  5 755-768
• 3 Galiè N, Olschewski H, Oudiz R J. et al, for the Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies (ARIES) Group . Circulation. 2008;  117 3010-3019
• 4 Galiè N, Manes A, Negro L, Palazzini M, Bacchi-Reggiani M L, Branzi A. A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.  Eur Heart J. 2009;  30 394-403
• 5 Galiè N, Rubin L j, Hoeper M. et al . Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial.  Lancet. 2008;  371 2093-2100
• 6 Ghofrani H A, Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy.  Eur Respir Rev. 2009;  18 35-41
• 7 Ghofrani H A, Hoeper M M, Hoeffken G, Halank M, Weismann G, Grimminger F. Riociguat dose titration in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH).  Am J Respir Crit Care Med. 2009;  179 A3337
• 8 Ghofrani H A, Morrel N W, Hoeper M M. et al . Imatinib in patients with severe pulmonary artery hypertension (PAH) refractory to standard therapy.  Am J Respir Crit Care Med. 2009;  179 A1044
• 9 Ghofrani H A, Seeger W, Grimminger F. Imatinib for the treatment of pulmonary arterial hypertension.  N Engl J Med. 2005;  353 1412-1413
• 10 Grimminger F, Weimann G, Frey R. et al . First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension.  Eur Respir J. 2009;  33 785-792
• 11 Hoeper M M, Mayer E, Simonneau G, Rubin L J. Chronic thromboembolic pulmonary hypertension.  Circulation. 2006;  113 2011-2020
• 12 Jaïs X, DŽArmini A M, Jansa P. et al, for the BENEFIT Study Group . Bosentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension.  J Am Coll Cardiol. 2008;  52 2127-2134
• 13 McLaughlin V V, Archer S L, Badesch D B. et al . ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association.  Circulation. 2009;  119 2250-2294
• 14 McLaughlin V V, Oudiz R J, Frost A. et al . Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2006;  174 1257-1263
• 15 Olschewski H. Inhaled iloprost for the treatment of pulmonary hypertension.  Eur Respir Rev. 2009;  18 29-34
• 16 Perros F, Montani D, Dorfmüller P. et al . Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2008;  178 81-88
• 17 Rich S, Rabinovitch M. Diagnosis and treatment of secondary (non-category 1) pulmonary hypertension.  Circulation. 2008;  118 2190-2199
• 18 Rosenkranz S. Pulmonary hypertension: Current diagnosis and treatment.  Clin Res Cardiol. 2007;  96 527-541
• 19 Rosenkranz S. Neue Konzepte in der Pathogenese der pulmonal arteriellen Hypertonie.  Dtsch Med Wochenschr. 2008;  133 (Suppl 6) S167-S169
• 20 Simonneau G, Robbins I M, Beghetti M. et al . Updated clinical classification of pulmonary hypertension.  J Am Coll Cardiol. 2009;  54 (Suppl S) S43-S54
• 21 Simonneau G, Rubin L J, Galiè N. et al, for the PACES Study Group . Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial.  Ann Intern Med. 2008;  149 521-530
• 22 Skoro-Sajer N, Hack N, Sadushi-Kolici R. et al . Pulmonary vascular reactivity and prognosis in patients with chronic thromboembolic pulmonary hypertension. A pilot study.  Circulation. 2009;  119 298-305
• 23 Ten Freyhaus H, Dumitrescu D, Bovenschulte H, Erdmann E, Rosenkranz S. Significant improvement of right ventricular function by imatinib mesylate in scleroderma-associated pulmonary arterial hypertension.  Clin Res Cardiol. 2009;  98 265-267
• 24 Ten Freyhaus H, Kappert K, Dagnell M, Leuchs M, Vantler M, Rosenkranz S. Hypoxia enhances PDGF signaling in the pulmonary vasculature by downregulation of protein tyrosine phosphatases (PTPs). (Abstract). Dana Point, CA; 4th World Symposium on Pulmonary Hypertension February 11 – 14, 2008
• 25 Voswinckel R, Enke B, Reichenberger F. et al . Favorable effects of inhaled treprostinil in severe pulmonary hypertension: results from randomized controlled pilot studies.  J Am Coll Cardiol. 2006;  48 1672-1681